Improved Synthesis of Capuramycin and Its Analogues

Wang, Yong; Siricilla, Shajila; Aleiwi, Bilal A.; Kurosu, Masaaki

doi:10.1002/chem.201302389

Cited by 21 publications

(24 citation statements)

References 72 publications

(75 reference statements)

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“…MurX enzyme inhibitory activity of tunicamycin ( 9 ) was determined to be the IC 50 value of 2.73 μM in which the observed activity of 9 was closely related to the data reported in the literatures (2.40-2.95 μM) [19]. In our screening of series of MraY inhibitors in enzyme and bacterial growth inhibitory assays, the MurX inhibitors that showed the IC 50 value of above 10 μM did not exhibit significant bactericidal activity against Mtb [46-48]. Thus, we set up an IC 50 threshold of 10 μM to distinguish exploitable antimycobacterial MurX inhibitors from other antimycobacterial molecules.…”

Section: Resultsmentioning

confidence: 55%

Biosynthesis of a water-soluble lipid I analogue and a convenient assay for translocase I

Siricilla

Mitachi

Skorupińska-Tudek

et al. 2014

Analytical Biochemistry

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Translocase I (MraY/MurX) is an essential enzyme in growth of the vast majority of bacteria that catalyzes the transformation from UDP-MurNAc-pentapeptide (Park’s nucleotide) to prenyl-MurNAc-pentapeptide (lipid I), the first membrane-anchored peptidoglycan precursor. MurX has been received considerable attentions to the development of new TB drugs due to the fact that the MurX inhibitors kill exponentially growing Mycobacterium tuberculosis (Mtb) much faster than clinically used TB drugs. Lipid I isolated from Mtb contains the C50-prenyl unit that shows very poor water-solubility, and thus, this chemical characteristic of lipid I renders MurX enzyme assays impractical for screening and lacks reproducibility of the enzyme assays. We have established a scalable chemical synthesis of Park’s nucleotide-Nε-dansylthiourea 2 that can be used as a MurX enzymatic substrate to form lipid I analogues. In our investigation of minimum structure requirement of the prenyl phosphate in the MraY/MurX-catalyzed lipid I analogue synthesis with 2, we found that neryl phosphate (C10-phosphate) can be recognized by MraY/MurX to generate the water-soluble lipid I analogue in quantitative yield under the optimized conditions. Herein, we report a rapid and robust analytical method for quantifying MraY/MurX inhibitory activity of library molecules.

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Section: Resultsmentioning

confidence: 55%

Biosynthesis of a water-soluble lipid I analogue and a convenient assay for translocase I

Siricilla

Mitachi

Skorupińska-Tudek

et al. 2014

Analytical Biochemistry

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“…[22], and its congeners are considered to be important lead molecules for the development of new drugs for Mycobacterium tuberculosis infections [23]. Accordingly, remarkable efforts have been devoted to establish convergent synthetic routes to access 5 that allow the preparation of analogues for SAR (structure-activity relationship) studies [24]. In this context, in 2009, Kurosu and co-workers described a concise synthesis of capuramycin (5), starting from the partially protected uridine 2 (15 steps), in which the primary amide unit was conveniently generated by the hydration of the C≡N unit of intermediate 3 using [PtH{(PMe2O)2H}(PMe2OH)] (1) (Scheme 3) [25].…”

Section: Preparation Of Complex [Pth{(pme 2 O) 2 H}(pme 2 Oh)] Firstmentioning

confidence: 99%

Synthetic Applications of the Parkins Nitrile Hydration Catalyst [PtH{(PMe2O)2H}(PMe2OH)]: A Review

Cadierno

2015

Applied Sciences

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Abstract:The air-stable hydride-platinum(II) complex [PtH{(PMe2O)2H}(PMe2OH)], reported by Parkins and co-workers in 1995, is the most versatile catalyst currently available for the hydration of C≡N bonds. It features remarkable activity under relatively mild conditions and exceptionally high functional group compatibility, facts that have allowed the implementation of this complex in the synthesis of a large number of structurally complex, biologically active molecules and natural products. In this contribution, synthetic applications of the Parkins catalyst are reviewed.

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“…We have generated a series of capuramycin analogues towards improving its in vivo efficacy (37,38). To identify WecA inhibitors, we applied the UV-Vis-based WecA assay to screen an optimized library of 50 capuramycin analogues in duplicate with 384-well plates.…”

Section: Resultsmentioning

confidence: 99%

“…UT-01320 ( 12 ) was resynthesized according to the procedures reported previously (37–39). Purity of 12 was determined to be over 98% via HPLC analysis (column: Kinetex 5u C18 100A, 250 × 4.60 mm, solvent: MeOH/H 2 O = 25/75, flow rate: 0.5 mL/min., UV: 254 nm).…”

Section: Methodsmentioning

confidence: 99%

Fluorescence-based assay for polyprenyl phosphate-GlcNAc-1-phosphate transferase (WecA) and identification of novel antimycobacterial WecA inhibitors

Mitachi

Siricilla

Yang

et al. 2016

Analytical Biochemistry

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Polyprenyl phosphate-GlcNAc-1-phosphate transferase (WecA) is an essential enzyme for the growth of Mycobacterium tuberculosis (Mtb) and some other bacteria. Mtb WecA catalyzes the transformation from UDP-GlcNAc to decaprenyl-P-P-GlcNAc, the first membrane-anchored glycophospholipid that is responsible for the biosynthesis of mycolylarabinogalactan in Mtb. Inhibition of WecA will block the entire biosynthesis of essential cell wall components of Mtb in both replicating and non-replicating states, making this enzyme a target for development of novel drugs. Here, we report a fluorescence-based method for the assay of WecA using a modified UDP-GlcNAc, UDP-Glucosamine-C6-FITC (1), a membrane fraction prepared from an M. smegmatis strain, and the E. coli B21WecA. Under the optimized conditions, UDP-Glucosamine-C6-FITC (1) can be converted to the corresponding decaprenyl-P-P-Glucosamine-C6-FITC (3) in 61.5% yield. Decaprenyl-P-P-Glucosamine-C6-FITC is readily extracted with n-butanol and can be quantified by ultraviolet-visible (UV-Vis) spectrometry. Screening of the compound libraries designed for bacterial phosphotransferases resulted in the discovery of a selective WecA inhibitor, UT-01320 (12) that kills both replicating and non-replicating Mtb at low concentration. UT-01320 (12) also kills the intracellular Mtb in macrophages. We conclude that the WecA assay reported here is amenable to medium- and high-throughput screening, thus facilitating the discovery of novel WecA inhibitors.

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Improved Synthesis of Capuramycin and Its Analogues

Cited by 21 publications

References 72 publications

Biosynthesis of a water-soluble lipid I analogue and a convenient assay for translocase I

Biosynthesis of a water-soluble lipid I analogue and a convenient assay for translocase I

Synthetic Applications of the Parkins Nitrile Hydration Catalyst [PtH{(PMe2O)2H}(PMe2OH)]: A Review

Fluorescence-based assay for polyprenyl phosphate-GlcNAc-1-phosphate transferase (WecA) and identification of novel antimycobacterial WecA inhibitors

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